The pancreas is a multifunctional gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland (producing several hormones including insulin, glucagon, and somatostatin), and an exocrine gland (secreting pancreatic juice containing digestive enzymes that pass to the small intestine). The enzymes in the pancreatic juice help in the further breakdown of the carbohydrates, protein, and fat in the chyme.
The part of the pancreas with endocrine function is made up of numerous cell clusters called islets of Langerhans. There are four main cell types in the islets classified by their secretion: α cells secrete glucagon, β cells secrete insulin, δ cells secrete somatostatin, and PP cells secrete pancreatic polypeptide. The islets are a compact collection of endocrine cells arranged in clusters and cords and also contain a network of capillaries. The capillaries of the islets are lined by layers of endocrine cells in direct contact with vessels, and most endocrine cells are in direct contact with blood vessels, by either cytoplasmic processes or by direct apposition.
In contrast to the endocrine pancreas, which secretes hormones into the blood, the exocrine pancreas produces digestive enzymes (e.g., trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, and amylase) and an alkaline fluid, and secretes these into the small intestine through a system of exocrine ducts in response to the small intestine hormones secretin and cholecystokinin. Digestive enzymes are produced and secreted by acinar cells of the exocrine pancreas. Specific cells that line the pancreatic ducts, called centroacinar cells, secrete a bicarbonate- and salt-rich solution into the small intestine.
Pancreatic dysfunction can lead to overproduction or underproduction of hormones and/or enzymes produced by the pancreas. Conditions associated with or caused by pancreatic dysfunction include diabetes mellitus, acute or chronic pancreatitis, pancreatic enzyme deficiency or pancreatic tumor.
Diabetes Mellitus (DM) is one of the most common chronic endocrine disorders across all age groups and populations, and is caused by pancreatic dysfunction. DM afflicts over 100 million people worldwide. In the United States alone, there are more than 12 million subjects diagnosed with DM, with 600,000 new cases diagnosed each year.
DM is a diagnostic term for a group of disorders characterized by abnormal carbohydrate (e.g., glucose) homeostasis or metabolism resulting in elevated blood sugar. These disorders comprise several interrelated metabolic, vascular, and neuropathic components. Various components of DM are caused by endocrine and/or exocrine functions of the pancreas. For example, the metabolic component, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced secretion of hormones, particularly insulin (i.e., endocrine function) and/or ineffective insulin action. At an exocrine level, the pancreas produces various enzymes that are involved in digestion of food. For example, the pancreas produces amylase and in DM may secrete insufficient levels of this enzyme to digest carbohydrate leading to exocrine pancreatic insufficiency, malnutrition and weight loss. Accordingly, both the endocrine and exocrine functions of the pancreas contribute to the metabolic components of DM. The vascular component of DM comprises abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also components of DM.
DM is generally caused by a reduction in the amount or circulating insulin and/or a reduction in the responsiveness of cells in a subject to insulin. Insulin is essential in the metabolism of carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and fat cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. Additionally, insulin slows the breakdown of protein for glucose production (gluconeogenesis). Insulin is produced and secreted by β cells in the islets of Langerhans of the pancreas.
There are several types of diabetes, including Type I (also referred to as insulin-dependent diabetes mellitus or IDDM) and Type II (also referred to as non-insulin-dependent diabetes mellitus or NIDDM), gestational diabetes and pre-diabetes (or impaired glucose metabolism). Of these, the two most common forms of diabetes are Type I and Type II diabetes. Type I diabetes (or insulin-dependent diabetes mellitus; IDDM) is caused by the absence, destruction, or loss of pancreatic β-cells resulting in an absolute deficiency of insulin. Type II diabetes (non-insulin dependent diabetes; NIDDM) is a heterogeneous disorder that is characterized by insulin resistance.
Type I Diabetes
The overall incidence of type I diabetes is approximately 15 cases per 100,000 individuals in the US alone. Approximately, 5 to 15 percent of all cases of diabetes are type I diabetes cases in the US, with physicians diagnosing about 10,000 new cases every year. Internationally, the incidence of type I diabetes varies from about 0.61 cases per 100,000 individuals in China to about 34.5 cases per 100,000 in Sardinia, and more than 40 cases per 100,000 in Finland. Many countries also report that the incidence rate of type I diabetes has doubled over the last 20 years.
The acute clinical onset of type I diabetes is characterized by symptoms, such as hyperglycemia, polyuria, polydipsia, weight loss, or blurred vision, alone or in combination, followed days or weeks later by ketoacidosis. Generally, the acute onset of the disease is considered to be preceded by a long, asymptomatic preclinical period, during which the insulin-secreting β-cells are progressively destroyed by the subject's immune system.
In healthy individuals, the pancreas normally contains 1 to 1.5 million islets; and approximately 80 percent of islet cells are insulin-producing β-cells. The symptoms of clinical diabetes appear when fewer than 10 percent of those β-cells remain.
The mismatch between insulin supply and demand caused by the loss of pancreatic β-cells leads to abnormal glucose, lipid and protein metabolism. Insulin deficiency may lead to hyperglycemia and hyperglycemic dehydration, elevated levels of free fatty acids, elevated serum ketone levels, increased levels of triglycerides, increased levels of very low density lipoproteins (VLDLs), increased levels of branched chain amino acids, a decrease in protein synthesis, and ketoacidosis. A subject with type I diabetes is likely to suffer from any one or more of a variety of vascular and neurologic complications. For example, type I diabetes patients are two times more likely than non-diabetics to have a heart attack; they are five times more likely to suffer from gangrene; seventeen times more likely to have complete renal failure, and twenty-five times more likely to lose their eyesight.
Treatment/Prophylaxis of Type 1 Diabetes
Currently, type I diabetes is treated by administration of exogenous insulin, exercise and dietary management. These forms of therapy do not correct the damage to the pancreas (i.e., replace the destroyed β-islet cells), but rather replace growth factors produced by the β-islet cells or attempt to avoid the requirement for these factors.
Most subjects suffering from type I diabetes require some form of insulin therapy. At this time, such therapy generally requires the subject monitoring blood glucose and/or insulin levels and injecting recombinant or purified insulin when required. New forms of insulin are also being developed to enable nasal or oral administration. However, this form of therapy requires continual monitoring by the subject and insulin administration at least once a day for the life of the subject. Should the subject neglect to administer insulin or administer too much insulin there is a risk of the development of, for example, hyperglycemia, hypoglycemia or ketoacidosis.
Additional compounds currently used for the treatment of type I diabetes include for example, sulfonylurea, biguanide, α-glucosidase inhibitor or thiazolidinedione. However, each of these compounds also suffers from significant disadvantages. For example, sulfonylurea causes hypoglycemia and hyperinsulinemia; biguanide causes lactic acidosis; α-glucosidase inhibitor causes gastro-intestinal side-effects; and thiazolidinedione has a long-onset of action, is associated with weight gain and requires frequent liver function testing.
Glucagon-like peptide-1 (GLP-1) has also been identified as a possible therapeutic for diabetes. This peptide induces expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a transcription factor that plays a significant role in pancreas development, beta cell differentiation and maintenance of beta-cell function (Babu et al., Mol Endocrinol. 20:3133-3145, 2006). PDX-1 is involved in inducing the expression of glucose sensing and metabolism, such as GLUT2, glucokinase and insulin. GLP-1 has been suggested as a potential therapeutic because it may induce pancreatic beta cell expansion in a subject, in addition to stimulating insulin expression (Buteau, Diabetes and Metabolism, 34: S73-S77, 2008). However, use of clinically available agents that increase intracellular availability of GLP-1, such as orally active dipeptidyl peptidase-4 (DPPIV) inhibitors or injectable GLP-1 analogs, has been limited to the treatment of mild forms of type II diabetes. The relatively short half-life of these agents, their need for frequent administration, and their relative lack of potency in cases of severe beta cell loss have precluded their use as insulin-sparing agents for type 1 diabetes or other insulin-dependent patients. Even orally available GLP-1 analogs have short half life and require high-dose daily administration.
Other therapeutic options include pancreatic islet of Langerhans transplantation, which has been shown to reduce insulin dependency (Shapiro et al., New Eng. J. Med., 343: 230-238, 2000). However, the application of this treatment is restricted by the very limited availability of primary human islets from donors, which must have a beating heart to ensure cell survival during transplantation (Burns et al., J. Endocrinology, 103: 437-443, 2004).
Stem cells, e.g., embryonic stem (ES) cells have also been proposed as a suitable source for the production of therapeutically relevant amounts of insulin-producing cells. However, insulin secreting β-cells have not been produced from stem cells, let alone at the level required, estimated at 2−4×109 β-cells per transplantation. Such cell-based therapies must also overcome such difficulties as the proliferative capacity of the replacement cells must be tightly controlled to ensure that they do not expand to a point that they cause hyperinsulinemia or hypoglycaemia, and the transplanted cells must avoid destruction by a recipient's immune system. Moreover, in the case of ES cell-based therapies, any remaining ES cells must be removed to avoid the risk of teratoma formation.
Type II Diabetes
Type II diabetes accounts for approximately 90-95% of diabetes cases and kills about 193,000 people per annum in USA alone. Type II diabetes is the seventh leading cause of all deaths. In Western societies, Type II diabetes currently affects 6% of the adult population with world-wide frequency expected to grow by 6% per annum. Notwithstanding that there are certain inheritable traits that may predispose particular individuals to developing Type II diabetes, the major cause of the current increase in incidence of the disease is the increased sedentary life-style, diet and obesity now prevalent in developed countries. Type II diabetes is now internationally recognized as one of the major threats to human health.
Type II diabetes, develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond (called insulin resistance) may be due to reduced numbers of insulin receptors on these cells, or a dysfunction of signaling pathways within the cells, or both. The β-cells initially compensate for this insulin resistance by increasing their insulin output. Over time, these cells become unable to produce sufficient insulin to maintain normal glucose levels, indicating progression to Type II diabetes (Kahn et al, Am. J. Med. 108: 2S-8S), 2000)
Treatment of Type II Diabetes
Conventional treatments for Type II diabetes are very limited, and focus on attempting to control blood glucose levels to minimize or delay complications. Current treatments target either insulin resistance (metformin, thiazolidinediones (“TZDs”)), or insulin release from the β-cells (sulphonylureas, exanatide). Sulphonylureas, and other compounds that act by depolarizing the beta cell, have the side effect of hypoglycemia since they cause insulin secretion independent of circulating glucose levels. Other side effects of current therapies include weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema.
One currently approved drug, Januvia (sitagliptin) increases blood levels of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well characterized effects. However, Januvia and other dipeptidyl peptidase IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated. Moreover, this compound does not address problems associated with insulin resistance.
As with type I diabetes, GLP-1 has been suggested as a potential therapeutic for type II diabetes as a result of its ability to induce insulin secretion, induce beta cell expansion and restore glucose tolerance in glucose-resistant beta cells. However, as discussed above, GLP-1 and analogs thereof are very limited in their therapeutic potential as a result of their very short half life.
It is clear from the foregoing that there is a need in the art for a method to treat or prevent or delay the onset or progression of disorders associated with pancreatic function and/or for improving pancreatic function.